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Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci

The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as...

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Detalles Bibliográficos
Autores principales: Dolan, David, Nelson, Glyn, Zupanic, Anze, Smith, Graham, Shanley, Daryl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566652/
https://www.ncbi.nlm.nih.gov/pubmed/23457464
http://dx.doi.org/10.1371/journal.pone.0055190
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author Dolan, David
Nelson, Glyn
Zupanic, Anze
Smith, Graham
Shanley, Daryl
author_facet Dolan, David
Nelson, Glyn
Zupanic, Anze
Smith, Graham
Shanley, Daryl
author_sort Dolan, David
collection PubMed
description The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system.
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spelling pubmed-35666522013-03-01 Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci Dolan, David Nelson, Glyn Zupanic, Anze Smith, Graham Shanley, Daryl PLoS One Research Article The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system. Public Library of Science 2013-02-06 /pmc/articles/PMC3566652/ /pubmed/23457464 http://dx.doi.org/10.1371/journal.pone.0055190 Text en © 2013 Dolan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dolan, David
Nelson, Glyn
Zupanic, Anze
Smith, Graham
Shanley, Daryl
Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title_full Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title_fullStr Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title_full_unstemmed Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title_short Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci
title_sort systems modelling of nhej reveals the importance of redox regulation of ku70/80 in the dynamics of dna damage foci
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566652/
https://www.ncbi.nlm.nih.gov/pubmed/23457464
http://dx.doi.org/10.1371/journal.pone.0055190
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